3,6-Bis-(aminoacylamino)-acridines

ABSTRACT

wherein R1 is hydrogen or methyl, R2 and R3, which may be identical to or different from each other, are each hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkylamino-lower alkyl, cycloalkyl, aralkyl, aryl or, together with each other and the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring system which may optionally contain one or more additional heteroatoms, and A is lower alkylene or aryl-lower alkylene, AND NON-TOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF; THE COMPOUNDS AS WELL AS THEIR SALTS ARE USEFUL AS INDUCERS OF THE FORMATION OF INTERFERON. Compounds of the formula

United States Patent [1 1 Cullen et al.

[ Sept. 23, 1975 [73] Assignees: Boehringer lngelheim Gmbl-l,

Ingelheim am Rhein; Dr. Karl Thomae GmbH, Biberach an der Riss, both of Germany [22] Filed: June 4, 1973 [21] Appl. No.2 366,732

[30] Foreign Application Priority Data June 7, 1972 Austria 4878/72 [52] U.S. Cl. 260/279 R; 260/243 B; 260/246 B; 260/268 TR; 424/246; 424/248; 424/257 [51] Int. Cl. C07D 219/06 [58] Field of Search 260/279 [56] References Cited OTHER PUBLICATIONS Ettel et al., Chem. Abstracts, Vol. 52, pp. 4642 & 4643-, (1968).

Primary Examiner-Donald G. Daus Assistant ExaminerD. B. Springer Attorney, Agent, or Firm-Hammond & Littell [57] ABSTRACT Compounds of the formula R is hydrogen or methyl,

R and R;;, which may be identical to or different from each other, are each hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkylamino-lower alkyl, cycloalkyl, aralkyl, aryl or, together with each other and the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring system which may optionally contain one or more additional heteroatoms, and

A is lower alkylene or aryl-lower alkylene,

and non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as their salts are useful as inducers of the formation of interferon.

5 Claims, No Drawings 3,G-BIS-(AMINOACYLAMINO)-ACRIDINES This invention relates to novel 3.(wbis- (aminoacylamino)-acridines and their acid .addition salts. as well as to methods of preparing these compounds.

More particularly. the present invention relates to a novel class of 3.6-bis-(aminoacyl-amino )-acridines rep resented by the formula R is hydrogen or methyl.

R and R which may be identical to or different from each other. are each hydrogen. lower alkyl. hydroxy-lower alkyl. lower alkylamino-lower alkyl. cycloalkyl. aralkyl. aryl or. together with each other and nitrogen atom to which they are attached. form a saturated or unsaturated heterocyclic ring system which may optionally contain one or more additional heteroatoms. and

A is lower alk yle'ne or aryl-lower alkylene. and nontoxic. pharmacologically acceptable acid addition salts thereof.

The compounds embraced by formula l may be prepared either by reacting a 3.6-his-(haloacyl-amino)- acridine of the formula wherein R and A have the same meanings as in formula l and X is chlorine. bromine or iodine, with an amine of the formula (Ill) In either case. the reaction is carried out at room temperature or elevated temperatures, optionally in the presence of an inert solvent medium and. if required. in the presence of an inorganic or organic base. such as sodium bicarbonate. potassium carbonate. sodium hydroxide. triethylamine or the like. Examples of suitable solvent media are ethanol. dimethylformamide. dimethylsulfoxide or the like. or mixtures of these; if the amine ofthe formula lll is itself a liquid at the reaction temperature. the presence of a separate solvent medium is not essential. provided that a sufficient excess of the liquid amine is present to act as the solvent medium.

The starting compounds embraced by formula 11 may be prepared by known methods. such as by acylation of a corresponding acridine derivative with free aminosubstituents of the formula IV under conventional acylation conditions. such as by reaction with an acyl halide or an acyl anhydride. preferably while heating.

The compounds of the formula I are organic bases and therefore form acid addition salts with inorganic or organic acids. Examples of non-toxic. pharmacologically acceptable acid addition salts are those formed with hydrohalic acids. nitric acid. sulfuric acid. orthophosphoric acid. oxalic acid. citric acid. tartaric acid.

fumaric acid. maleic acid. propionic acid. butyric acid. acetic acid. methanesulfonic acid. succinic acid. 8- chlorotheophylline or the like.

Using the above-described methods. the following compounds can be prepared:

3 .6-bis-l (N.N-dimethylamino )-acetylamino wherein R and R have the same meanings as in foracridinemula l; or by reacting a 3 .o-diamino-acridine of the for- 3.6-bis-[(N-ethylamino)-acetylamino]-acridine. mula 3.6-bis-l N.N-diethylamino)-acetylamino Lacridine.

R i R l l wherein R has the meanings previously defined. with 3.6bis-[(N.N-diethylamino)-acetylamino]-2.7- an aminoester of the formula dimethyl-acridine.

O 3.6-bis-[3-(N.N-diethylamino)-propionylamino]- H acridine. N- \--(-()R (V) 3,6-b1s-[2-(N.N-diethylarnino)-prop1onylammo]- acridine, wherein R R and A have the meanings previously de- 3.6-bis-[4-(N.N-diethylamino)-butyrylamino]- fined and R is lower alkyl. acridine.

3.6-bis-l N.N-dicthylamino )-tcrt.butyrylamino acridine.

3.6-bis-l 5-( N,N-diethylamino )-valcroylamino lacridine.

3.6-bis-l (N-methyl-N-2-hydroxyethylamino acetylamino I-acridine. I

3.6-bis-l (u-NN-diethylamino )-phenylacetamido acridinc.

3 .b-his-l (N.N-din-propylamino )-acetylamino lacridinc.

3.6-bis-I (N.N-di-isopropylamino )-acetylamino acridinc.

3.6-bis-l (N.N-di-n-butylamino )-acetylamino acridinc.

3,6-bis-l (N.N-di-n-hexylamino)-acetylamino acridinc,

3.6-bis-[ (N-n-propylamino )-acetylamino l-acridine.

3.6bis-[ N-isopropylamino )-acctylamino l-acridine,

3.6bis-l N-n-butylamino )-acetylamino l-acridine.

3,6-his-1(N-n-hexylamino)-acetylaminol-acridine.

3.6-bis-l N.N-diallylamino)-acctylamino l-acridine.

3,6-his-l (N-cthyl-NZ-hydroxyethylamino acetylaminol-acridine.

3.6-bis-l N.N-di-2-hydroxyethylamino) acetylamino)-acridine.

3.6-bis [N-( N.N-diethylamino )-propylamino acety amino -acridine.

3,6-bis{ lN-methyl-N-(N,N'-dicthylamino)- propylaminol-ac'etylamino -acridine.

3.6-bis-l(N-cyclohexylamino)-acetylamino]- v acridine.

3.6-bis-l N-methyl-N-cyclohexylamino)'r acetylaminol-acridine.

.3.6-bis-[(N-ethyl-N-cyclohexylamino)- acetylaminoI-acridine.

3.6-bis-l N-propyl-N-cyclohexylamino)- acetylaminol-acridine.

3.6-bis-l N-isopropyl-N-cyclohexylamino acetylaminol-acridine.

3.6-bis-l N-n-butyl-N-cyclohexylamino)- acetylaminol-acridine.

3.6-bis-l(N.N-di-cyclohexylamino)-acetylamino1- acridine,

3.6-bis-l N-ethyl-N-cyclopentylamino acetylaminol-acridine.

3 ,6-bis-l N-n-propyl-N-cyclopentylamino acetylaminol-acridine,

3.6-bis-l N-n-butyl-N-cyclopentylamino acetylamino1-acridine.

3,6-bis-l N-benzylamino )-acetylamin0 l-acridine,

3.6-bis-l N-methyl-N-benzylamino )-acetylamino]- acridine.

3.6-bis-l N.N-dibenzylamino )-acetylamino acridine,

3 ,6-bis-[ 2-( N-methyl-N-cyclohcxylamino propionylaminol-acridine.

3 ,6-bis-l N-methyl-N-phenylamino propionylaminol-acridine.

3 ,6-bis-( pyrrolidino-acetylamino )-acridine,

Y 3,6-bis-[Z-(piperidino)-propionylaminol-acridine.

4. 3,6-his-l (3 '-'mcthylpipcridino )-acc'tylamim)'|' acridinc, 3,6-bis-l (2'methylpipcridino )'-acetylamino lacridine. 1 3.6-bis-l (4-mcthylpiperidino )-acetylamino I acridinc. 3.6-bis-l 3 '-h \'droxypiperidinol-acctylami'no acridinc. I 3.6-his-l (4'-ethoxycarbonylpipcridino acctylamino l-acridinc. 3.6-bis-l (4'-hydrosymethylpipcridino acetylamino l-acridine. 3,o-his-( l 2.5.(w-tetrahydropyridino-acctylamino acridine. 3.6-bis-( hexamethylencimino-aectylamino )-acridine. 3.6-bis-l(4-B-hydroxyethyl-pipcrazino)- acetylamino l-acridine. 3.6-bis-( morpholino-acetylamino )-acridinc. 3.6-bis-[ N-thiomorpholino l-acctylamino l-ac-ridine. 3.6-bis-l (N-thiomorpholino-S-oxidc)atcetylamino lacridine. 3.6-bis-l N-thiomorpholino-S.S'dioxide acctylaminol-acridinc, I 3.6-bis-( piperidino-acetylamino lfacridine. and their non-toxic. pharmacologically acceptable acid addition salts.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should he understood. however. that the invention is not limited solely to the particular examples given below.

EXAMPLE I 3.6-Bis-( morpholinoacetyl-amino )-acridine trihydrochloride dihydrate which had a melting point of 300C.

The starting compound. 3.6-bis-(chl0roacetylamino)-acridine. was prepared in conventional manner by acctylating proflavin with chloroacetyl chloride or chloroacetic acid anhydride.

EXA PLE 2 I 3.6-Bis-[t N.N-diethylamino-acetyl )-amino]-acridine trihydrochloride A mixture consisting of 18.2 gm of 3.6-bis- (chloroacetyl-amino)-acridine. 36.5 gm of diethylamine and 100 ml of dimethylformamide was stirred for 4 hours at 100C. and then allowed to stand overnight at room temperature. Thereafter, lOO ml of ethyl acetate were added to the reaction mixture. the diethylamine hydrochloride precipitated thereby was filtered off. the EXAMPLE 5 filtrate was acidified with saturated ethereal hydrochlo- 3.(i-Bis[ 3 -N.N-diethylamino-propionyl )-amino ric acid. and the precipitate formed thereby was eolitcridin triln'drochloridc dihydrate leeted by filtration. washed with ether. and reerystal- 5 lllcfl lmm mclhiuml present of animal Char 3.6 gm ofdimethylamine were added to a suspension coal The crystals were extracted with a mixture of i f 3 gm f 35-1 1 4 3 hl i l m chloroform and methanol (9:1 in a Soxhlet apparatu acridine hydrochloride in ml of dimerhyltorimrmide. the extracts were evaporated to dryness. and the resiand the solution formed thereby was heated for 2 hours due was recrystallized from methanol. yielding the at 95C on a water bath. Thereafter. the reaction solucompound of the formula tion was evaporated in vacuo until a thick oil remained.

N-H C- HN NH--iICH N .3Hc1 H50; z s

. /iCH OH which had a melting point of 287C (decomp.)t 20 water was added to this oil. and the precipitate formed thereby was collected by filtration and crystallized EXAMPLE 3 twice from acetonitrile. yielding the free base 3.6-hisl(3'N.N-diethylamino-propionyl )-amino l aeridine.

3.6-Bis-[(N.N-dimeth lamino-acet l)amino]-acridine y y 1 The base was dissolved in chloroiorm. gaseous hydrotrlhydmchlondc gen chloride was passed through the solution. and the A mixture consisting of L85 gm of 3.6-bisprecipitate formed thereby was collected. washed and (chloroacetyl-aminoJ-aeridine hydrochloride. 3.0 gm dried. yielding l.l gm of the compound of the formula O ii C H :NCH CH C HN N NHC-CH CH N 2 .3HCI CgHs z s 35 otdimethylamine and 10 ml ofdimethylformamide was which had a melting piont of 23924lC. heated for two hours at [00C in a pressure vessel and The starting compound was prepared in conventional was then allowed to stand overnight at room temperamanner from Pmflilvlnc p p y ture. Thereafter. 2() ml of ethyl acetate were added to ridethe reaction mixture. the precipitate formed thereby 4O EXAMPLE 6 was filtered off. and the filtrate was acidified with an 3 Bi N N-dil i l j iexcess of ethereal hydrochloric acid. The crystals ridine trihydrochloride hemihydrate whichlisepairatedout were clollecfed by filtllIlOtlilflEl re- A mixture Consisting 0f .8 g 36 bis mu Ail/Her lwlce mm (chloroaeetyl-amino)-acridine hydrochloride, 3.0 gm

dioxane/wat er. y g 9 P of di-n-propylamine and It) ml of dimethyli'ormamide d1methylamtno-acetyl)-ammo]-acr1dme trihydrochlowas heated for three hourS on a huiling water bath ride which had a melting POint above 300C Thereafter. the unreacted excess ofdipropylamine was i evaporated. and ethereal hydrochloric acid was added to the residual mixture. The oil formed thereby was taken up in chloroform. the resulting solution was fil- EXAMiPLE 4 tered through animal charcoal. and ethyl acetate was added to the filtrate. The precipitate formed thereby was collected, dissolved in isopropanol. reprecipitated by addition of ethyl acetate and again collected, treated A mixture consisting of gm of with hot acetonitrile. filtered off. washed and dried. (ichloroacetyl-amino)-acridine hydrochloride. 3 gm of yielding 0.9 gm of 3.6-bis-[(N,N-di-n-propylamino- 3.6-Bis-l (N-ethylamino-acetyl )-amino ]-acridine trihydrochloride ethylamine and 10 ml of dimethylformamide was acetyl)-amino]-acridine trihydrochloride hemihydrate heated for 2 hours at 100C in a pressure vessel and was which had a melting point of l-210C (decomp.). then allowed to stand at room temperature overnight. EXAMPLE 7 Thereatter, the unreacted excess of ethylamme was CllS- tilled off in vaCuO, the residue, 3.6-bis-[(N-ethylamino- -t( y -p p y tr acetyl)-amine]-acridine. was converted into its trihyacrldlne trihydrochloride dlhydrme drochloride by addition of cthanolic hydrochloric acid, 3 6 gm f di h l mine were added to a solution of and the salt was recrystallized 3 times from dioxanel- 65 2.4 gm of 3.6-bis-(a-bromopropionyl-amino)-acridine water. whereupon it had a melting point of 280C (dein 20 ml dimethylformamide, and the resulting mixture comp). The yield was 1.1 gm. was heated for 2 hours at C on a water bath. There after. thereaction mixture was concentrated in vacuo until. an oil remained. and this oil was admixed with water whereby a solid substance was formed which was filtered off. washed. dried and crystallized from ethanol. I The crystals. 3.6-bis-[(Z-N.N-diethylamino-prm pionyl )-amino]-acridine. were dissolved in chloroform. the resulting solution was acidified withvan excess of 2 N ethereal hydrochloric acid. the precipitate formed thereby was collected and redissolved in hot isopropanol. the resulting solution was treated with animal char-.

coal. and the product was reprecipitated by addition of I ethyl acetate. yielding 1.0 gm of the compound of the formula i 3.6 gm of diethylamine were added to a solution of l 2.6 gm of 3.6-bis-(a-chloro-phenylacetamido )acridine in ml of dimethylformamide. and the mixture was heated for 2 hours at 95C on a water bath. Thereafter. the reaction mixture was evaporated until a thick oil remained to which 50 ml of acetyl acetate and then ethereal hydrochloric acid were added. The precipitate formed thereby was collected by filtration. dissolved in water. the aqueous solution was made alkaline with ammonia. and the precipitate formed thereby was filtered off and recrystallized 3 times from ethanol. yielding l .8 gm of the free base of the formula which had a melting point of 250255C The starting compound. 3.6-bis-(a-bromopropionylamin0)-acridine. was prepared in conventional manner from proflavine and 2-bromo-propionyl bromide.

EXAMPLE 8 3 .6-Bis-[ N-methyl-N-fi-hydroxyethyl-amino )-acetylaminol-acridine and its trimaleate hydrate A mixture consisting of 4.35 gm of 3.6-bis- (chloroacetyl-amino)-acridine. 5.5 gm of potassium carbonate. 1.88 gm of N-methyl-N-B-hydroxyethylamine and 50 ml of dimethylsulfoxide was stirred overnight at room temperature. Thereafter. the reaction 40 mixture was poured over ice. and the precipitate formed thereby was collected. washed and recrystallized from ethanol/ether. yielding 2.4 gm of the free base of the formula I which had a melting point of l83l85C.

500 mgm of the twice recrystallized free base were suspended in acetone and. while stirring the suspension. a solution of 530 mgm of maleic acid in 5 ml of acetone was added. The mixture was stirred overnight. and the precipitate formed thereby was collected by filtration. washed and dried. yielding 720 mgm of the trimaleate hydrate of the base. which had a melting point of ll46C.

EXAMPLE 3.6-Bis-[(q-N.N-diethylamino-phenylacetamido acridine and its trimaleate hemihydrate The starting compound. 3.6-b'is-( a-chlorophenylacetamido)-acridine. was prepared in conventional manner from proflavine and "oz-chlorophenylacetyl chloride. I I

EXAMPLE '10" 3 .o- Bis-l N-ethyl-N-B-hydroxyethylamino-acetyl aminol-acridine and its trimal eate CH NH-C CH,N n.2,

CH2CH2OH A mixture consisting of 3.0gm of 3.6-bis- (chloroacetyl-amino)-acridine and 15 ml of N-ethyl-N-B-hydroxyethylamine was stirred for'4 hours at room temperature. Thereafter. theclear syrupy solution which was formed thereby was diluted with 500 ml of chloroform and washed with water. The chloroform phase was dried and-evaporated to dryness in vacuo. and the residue (4.0 gm') was crystallized twice from ethanol. yielding 1.7 gm of the free base of the formula which had a melting point of l" l76C.

L6 gm of the free base were suspended in acetone. and the suspension was admixed with an excess (1.4

gm) of maleic acid. and the mixture was stirred for five 3 EXAMPLE 13 hours. Thereafter. the precipitate was collected by filtration. washed with acetone and dried. yielding 2.6 gm ofthe trimaleate of the base. which had a melting point ml (01 1 0f Piperldine were added t0 11 Soil! of l26l 30C. tion of 4.0 gm (0.01 I mol) of 3.6-bis- (chloroacetylamino)-acridine in dimethylformamide. EXAMPLE 1 1 and the mixture was heated at 100C for about 4 hours. Thereafter. the reaction mixture was allowed to cool and was then admixed with 22 ml of ethyl acetate. The pipcridine hydrochloride which separated out slowly 3 .6-Bis-( piperidinoacetyl-amino )-acridine 3.6-Bis-l N.N-di-B-hydroxyethylamino-acetyl aminol-acridine and its trimalcate H A mixture consisting of 4.35 gm of 3.6-biswas separated by vacuum filtration. The clear filtrate (chloroacetyl-amino)-acridine. 5.5 'gm of potassium was admixed with ethereal hydrochloric acid until the carbonate. 2.62 gm of diethanolamine and 22 ml of dimixture reacted strongly acidic. and the precipitate methylsulfoxide was stirred overnight at room temperaformed thereby was collected by vacuum filtration. ture. then filtered. and the filtrate was poured over ice. l5 washed with an ample amount of ether and dried. The The precipitate formed thereby was collected by filtrasubstance thus obtained was dissolved in 750 ml of wation. washed. and recrystallized once from ethanol and ter. and the resulting solution was admixed dropwise three times from methanol. yielding 3.5 gm of the free with 50 ml of aqueous 71 ammonia. accompanied by base of the formula vigorous stirring. A brownish oil separated out which O O HOH4C-,\ ii ll /C2H4OH NCH CHN N NH-.-C-CH N HOH4C2 (.zl'hOH which had a melting point of 175C (sinters at 165C). gradually crystallized throughout. and the crystallizate 350 mgm of the free base were dissolved in 8 ml of was collected. thoroughly washed with water and dried acetone. 350 mgm of maleic acid were added to the soat room temperature in vacuo over phosphorus pentoxlution. and the mixture was allowed to stand at room ide. yielding 4.94 gm (97.3% of theory) of raw 3.6-bistemperature for four hours. Thereafter. the precipitate w (piperidinoacetyl-amino)-acridine of the formula which had formed was collected by filtration. washed The raw product was recrystallized twice from ethanol. and dried. yielding the trimaleate of the base. which yielding 82% of theory of the pure product which had had a melting point of l-l 3 lC (sintering beginning a melting point of 192-l94C. at 122C). a

EXAMPLE l4 EXAMPLE l2 Using a procedure analogous to that described in Ex- 3.6-Bis- {[Nmethyl-N-(N.N'-diethylamino)-N-propylample 13 3457, of theory f 3 amino]acetylamino} acridine and its pentamaleate diisgprgpylumino-acetyl) aminol-ucridine h d m.p. l23l26C (recrystallized from ethanol/water).

was obtained from 3.6-bis-(chloroacetyl-amino)- acridine and diisopropylamine.

A mixture consisting of 1.1 gm of (chloroacetyl-amino)-acridine. 800 mgm of ldiethylamino-3-methylamino-propane. 1.1 gm of po tassium carbonate and 20 ml of dimethylsulfoxide was 5 stirred overnlght at room temperature. Thereafter, the 50 EXAMPLE reaction mixture was diluted with 200 ml of ethyl ace- Using a procedure analogous to that described in Extate. washed with water, dried and evaporated to dry ample 13. 78.5% of theory of 3.6-bis-l (N.N- ness. The residue, i.e. the raw free base of the formula dibutylaminoacetyl)-amino]-acridine. m.p.

II ll was dissolved in ethanol. the solution was admixed with ll47C (recrystallized from ethanol/water). was a slight excess of an ethanolic solution of maleic acid. obtained from 3.6-bis-(chloroacetylamino)-acridine and the precipitate formed thereby was collected by filand dibutylamine. tration. washed and recrystallized twice from ethanol in 5 the presence of animal charcoal. yielding l.9 gm of the EXAMPLE l6 p entamaleate ofthe base. which had a melting point of Using a procedure analogous to that described in Ex- 98l()lC. ample 13. 49% of theory of 3.6-bis-[(N.N-diallylaminoacetyl )-amino l-aeridine. m.p. l()2l 03C (recrystallized from ethanol/water). of the formula was obtained from 3 (1-bis-(chloroacetyl-amino)- acridine and diallylamine.

EXAMPLE 17 Using a procedure analogous to that described in Example l3. 65% of theory of 3.6-bis-l (N.N-di-n-hexylaminoacetyl)-aminol-acridine. m.p. 9596C (re- 15 crystallized from ethanol/water, was obtained from 3.6- his-(chloroacetyl-amino)-acridine and di-nhexylamine.

EXAMPLE 18 Using a procedure analogous to that described in Example l3. 91% of theory of 3.6-bis-[(pyrrolidinoaeetyll-aminol-acridine. m.p. l9l-l93C (recrystallized from ethanol/water) of the formula T ll ll was obtained from 3.6-bis-(chloroacetyl-amino)- acridine and pyrrolidine.

EXAMPLE 9 Using a procedure analogous to that described in Example I3. 78% of theory of 3.6-bis-I(N-cyclohexyl-N- methylamino-acetyl )-amino I-acridine. m .p. l67l69C (recrystallized from ethanol/water). of the formula was obtained from 3,6-bis-(chloracetyl-amino)- acridine and N-cyclohexyl-methylamine.

EXAMPLE 20 Using a procedure analogous to that described in Example I3, 68% of theory ol- 3.6-bis-[(N-benzyl-N- methylamino-acetyl)-amino]-acridine. m.p. 6

l42l45C (recrystallized from ethanol/water). of the formula was obtained from 3 6-bis-(chloroacetyl-amino) acridine and N-benzyl-methylamine.

EXAMPLE 22 Using a procedure analogous to that described in Example I3. 29% of theory of 3.6'-bis-[(N-phenyl-N- methylamino-acetyl)-amino]-acridine, m.p. l55l57C (recrystallized from ethanol, of the formula was obtained from 3.6-bis-(chloroacctyl-amino)- acridine and N-methyl-aniline.

EXAMPLE 23 Using a procedure analogous to that described in Example l3. 62% of theory of 3,6-bis-l(N-cyclohexyl-N- cthyl-amino-acetyl)-amino]-acridine hemihydrate. an

45 amorphous powder (precipitated from dilute hydrochloric acid with aqueous ammonia), was obtained from 3,6-bis-(chloroacetyl-amino)-acridine and N- cyclohexyl-ethylamine.

EXAMPLE 24 Using a procedure analogous to that described in Example l3, 71% of theory of 3.6-bis-l(N-eyclohexyl-N- n-propyl-amino-acetyl)-amino]-acridine hemihydrate.

an amorphous powder (precipitated from dilute hydrochloric acid with aqueous ammonia), was obtained from 3,6-bis-(chloroacetyl-amino)-acridine and N-cyclohexyl-n-propylamine.

EXAMPLE 25 Using a procedure analogous to that described in Example l3. 7l'/( of theory of 3,6-bis-l(N-cyclohexyl-N- n-butyl-amino-acetyl)-aminol-acridinc. m.p. l79l82C (recrystallized from cthanol/dioxane/water), was obtained from 3.6-bis-(chloroacetyl-amino)- acridine and N-cyclohexyl-n-butylamine.

EXAMPLE 26 Using a procedure analogous to that described in Example 13, 5871 of theory of 3,6-bis-[(N-cyclopentyl-N- n-butyl-amino-acetyl)-amino]-acridine hemihydrate. an amorphous powder (precipitated from dilute hydrochloric acid with aqueous ammonia), was obtained from 3 ,6-bis-( chlortmcetyl-amino )-acridine and N-cyclopentyl-n-butylamine.

EXAMPLE 27 3.6-Bis[ (N-adamantylamino-acetyl )-amino]-acridine hydrate A mixture consisting of 3 gm of 3.6-bis-(chloroacetyl-amino)-acridine, 50 ml of dimethylformamide and 6 gm of l-adamantanamine was heated for 5 hours at 80C. Thereafter. the reaction mixture was allowed to stand for a few days at room temperature and was then stirred into water. The precipitate formed thereby was collected and dried, yielding 2871 of theory of an amorphous substance which was identified to be 3,6-bis- [(N-adamantylaminoucetyl)-amino]-acridine hydrate.

EXAMPLE 28 dissolved in 250 ml ofhot dioxane, and the solution was admixed with 500 ml of dilute ammonia, whereby an amorphous precipitate was formed which graduallywith a melting point of l77l 79C was obtained.

EXAMPLE 2) Using a procedure analogous to that described in Example 28, 7371 of theory of 3,6-bis-l(thiomorpholinoacetyl )-amino l-acridine hemihydrate. m .p. l40l50C (recrystallized from dioxane/ethanol/dilute ammonia), was obtained from 3.6bis-(chloroacetyl-amino)-acridine and thiomorpholine.

EXAMPLE 30 Using a procedure analogous to that described in Example 28, 83% of theory of 3.6-bis-l(thiomorpholino- S.S-dioxide-acetyl)-amino]-acridine hydrate. m.p ll92C (recrystallized from dioxane/ethanol/dilute ammonia). was obtained from 3.6-bis-(chloroacetyl-amino)-acridine and thiomorpholine-S.S-dioxide.

EXAMPLE 31 Using a procedure analogous to that described in Example 28, 76% of theory of 3.6-bis-[(cyclohexylaminoacetyl)-amino]-acridine. m.p. EST-255C (recrystallized from ethanol/dilute ammonia), was obtained from 3.6-bis-(chloroacetyl-amino)-acridine and cyclohexylamine.

EXAMPLE 32 Using a procedure analogous to that described in Example 28, 56% of theory of 3,6-bis-[(isopropylaminoacetyl)-amino]acridine, m.p. 233-236C (recrystallized from ethanol/dilute ammonia), was obtained from 3,6-bis-(chloroacetylamino)-acridine and isopropylamine.

EXAMPLE 33 3 ,o-Bis- 3 '-methylpiperidino-acetyl )-amino ]-acridine hemihydrate A mixture consisting of 4.0 gm (0.011 mol) of 3,6- bis-(chloroacetyl-amino)-acridine, 4.0 gm (0.04 mol) of 3methyl-piperidine and 25 ml of dimethylformamide was heated for 3 hours at 60C. Thereafter. the clear reaction solution was introduced into 200 ml of dilute aqueous ammonia, accompanied by vigorous stirring. and the yellow precipitate formed thereby was collected by vacuum filtration. washed with water. dried in vacuo over phorphorus pcntoxide at room temperature, and recrystallized first from 40 ml of hot cthanol and then from ml of water. 7 1% of theory of the compound of the formula crystallized throughout Careful concentration of the solution to about 400 ml in vacuo at 60C accelerated the crystallization. 68% of theory of the compound of the formula with a melting point of 97-l02C was obtained.

EXAMPLE 34 Using a procedure analogous to that described in Example 33, 75% of theory of 3,6-bis-[ (2'-methyl piperidinoacetyl )-amino]-acridine hemihydrate,= m.p.

l 28- -I 30C (recrystallized from ethanol/dilute ammonia). was obtained from 3.6-bis-(chloroacetyl-amino)- acridine and Z-methyl-piperidine.

' EXAMPLE was obtained from 3.6-bis-(chloroacetyl-amino)- acridine and 4-ethoxycarbonyl-piperidine.

EXAMPLE 37 Using a procedure analogous to that described in Example 33, 71% of theory of 3,6-bis-I l ,2',5',6 tetrahydropyridino-acetyl )-amino l-acridine hemihydrate, m.p. 95l()()C (recrystallized from ethanol/water), was obtained from 3,6-bis-(chloroacetyl-amino) acridine and l,2.5.o-tetrahydropyridine.

EXAMPLE 38 Using a procedure analogous to that described in Example 33, 49% l of theory of 3,6-bis-[(N-B- hydroxyethyl-piperazino-acetyl)-amino]-acridine dihydrate, m.p. 228233C (recrystallized from ethanol). of the formula v 16 -acridine l A H O, m.p. 145 -150 C (recrystallized from methanol/water), was obtained from 3,6-bis- (chloroacetylamino)-acridine and 4-hydro ty-methylpiperidine. 1

EXAMPLE 4,1

Usinga' proced ure ana'logbus to that described in Example 33, 89% of' theory of 3,6-bis-[ benzylaminolized from dioxane/ethanol/water). was obtained from 3,6-bis-(chloroacetyl-amino)-acridine and benzylamine.

EXAMPLE42" Using a procedure analogous to that described in Example 33, 75% of theory of 3;6-bis-l(n-butyl-aminoacetyl)-amino]-acridine,' m.p. l82l 859C (recrystallized from cthanol/dioxane/water). was obtained from 3 ,6-bis-( chlo roacetyl-amino )-acridin e 7 and nbutylamine.

EXAMPLE 43 Using a procedure analogous to that described in Example 33, 8l% of theory of 3 ,6 .bis-[(n-propyl-aminoacetyU-aminol-acridine. m.p. l85l 87C. (recrystallizedfrom dioxane/water/ethanol), was obtained from 3,6-bis-(chloroacetyl-amino)-acridine and npropylamine.

EXAMPLE44- Using a procedure analogous to that described in Example 33, 66% of theory of 3,6-bis-[(n-h,exylaminoacetyl)-amino]-acridine, mp. l82'-l85C (recrystallized from ethanol/water), was obtained from 3,6-bis- (chloroacetyl-amino)-acridine and n-hexylamine.

was obtained from 3.6-bis-(chloroacetyl-amino)- acridine and 4-[3-hydroxyethyl-piperazine.

EXAMPLE 39 Using a procedure analogous to that described in Example 33. 7571 of theory of 3,6-bis- [(hexamethyleneimino-acetyl)-amin0]-acridine. m.p. l9()193C (recrystallized from ethanol/water), was obtained from 3,6-bis-(chloroacetyl-amino)-acridine and hexamethyleneimine.

EXAMPLE 4() Using a procedure analogous to that described in Example 33, 71% of theory of 3,o-bis-[(4'- hydroxymethyl-piperidino-acetyl )-amino l-acridine.

EXAMPLE 45 Using a procedure analogous to that described in Example 33, 83% of theory of 3.6-bis-[(N-cyclohexylcyclopropylamino-acetyl)-amino]-acridine, an amorphous powder (precipitated from dimethylformamide/- methanol/water). was obtained from 3.6-bis- (chloroacetyl-amino )-acridine and N-cyclohexylcyclopropylamine.

EXAMPLE 46 Using a procedure analogous to that described in Example 33, 49% of theory of 3.6-bis-[(N'-methylpiperazino-acetyl)7amino]-a cridine hemihydrate. m.p. 232235C (recrystallized from water), was obtained from 3,6-bis-(chloroacetyl-amino)-acridine and N-methyl-piperazine.

EXAMPLE 47 3 .o-Bis-l 3 '-hydroxypiperidino-acetyl )amino l-acridine hemihydrate A solution of 4.0 gm (0.0ll mol) of 3.6-bis- 5 (chloroacetyl-amino)-acridine in 25 ml of dimethyl l'orrnamide was admixed with 40 gm (0.039 mol) of 3- hydroxy-piperidine. and the mixture was heated for 3 hours at 80C. After the reaction had gone to completion. the reaction mixture was concentrated to about ml by evaporation in vacuo. and then 200 ml of acetone as well as 40 ml of ethereal hydrochloric acid were added. The yellow precipitate formed thereby was collected by vacuum filtration. washed with water. dried and dissolved in 150 ml of hot water. While stirring the aqueous solution. 30 ml of aqueous ammonia were added. and the precipitate formed thereby was collected and crystallized first from 20 ml of ethanol and then from 50 ml of dilute ammonia. yielding 86% of theory of the compound of the formula 20 which had a melting poing of l28-l 30C.

3.6-Bis-la-(2-methylpiperidino)-propionyl-amino]- acridine hemihydrate A mixture consisting of 6.0 gm of 3.6-bis-(achloropropionyl-amino)-acridine. l5.2 gm of 2-methylpiperidine and 50ml of dimethylformamide was heated for 5 hours at 100C. Thereafter, the reaction mixture was concentrated by evaporation in vacuo to a small volume. admixed with 150 ml of ethyl acetate, and the 2methylpiperidine hydrochloride precipitated thereby was separated by filtration. The filtrate was evaporated. the residue was dissolved in 100 ml of ethanol at 80C. and the solution was admixed with about ml of water until it started to turn cloudy. The precipitate formed thereby was collected and recrystallized from ml of ethanol and 30 ml of water. yielding 6.55 gm (8271 of 55 theory) of the compound of the formula propionyl-aminol-acridine hydrate. m.p. l9720lC (recrystallized from ethanol). was obtained from 3.6- bis-(oz-chloropropionylamino)-acridine and piperidine.

EXAMPLE 51 Using a procedure analogous to that described in Ex ample 49. 58% of theory of 3.o-bis-[a-(3- methylpiperidino)-propionyl-aminol-aeridine hydrate. m.p. l60l64C (recrystallized from ethanol). was obtained from 3 .6-bis-( oz-chloropropionyl-amino acridine and 3-methyl-piperidine.

EXAMPLE 52 Using a procedure analogous to that described in Example 49. 5671 of theory of 3.6-his-[a-(4'- methylpiperidino)-propionyl-aminol-acridine hydrate. m.p. l82-l86C (recrystallized from ethanol/water). was obtained from 3,6-bis-(oz-chloropropionyl-amino)- acridine and 4-methyl-piperidine.

EXAMPLE 53 Using a procedure analogous to that described in Example 49. 5871 of theory of 3.6-bis-{oz-( l ,2.5.6'- tetrahydropyridino)propionyl-amino]-acridine hemi hydrate. an amorphous powder (precipitated from dilute hydrochloric acid with aqueous ammonia). was ob tained front 3.6-bis-(a-chloropropionyl-amino)- acridine and l,2,5.6-tetrahydropyridine.

EXAMPLE 54 Using a procedure analogous to that described in Example 49. 59% of theory of 3.o-bis-lcx-(N-cyclohexyl methyl-amino)-propionyl-amino]-acridine. m.p. 85-90C (recrystallized from ethanol/water). was obtained from 3.6bis-(a-chloropropionyl-amino)- acridine and N-cyclohexyl-methylamine.

EXAMPLE 55 Using a procedure analogous to that described in Ex ample 49. 56% of theory of 3.6-bis-[a- (cyclohexylamino)-propionyl-amin0l-acridine hydrate. m.p. ll84C (recrystallized from ethanol), was obtained from 3,6-bis-(a-chloropropionylamino)- acridine and cyclohexylamine.

EXAMPLE so.

Using a procedure analogous to that described in Example 49. 68% of theory of 3.6-bis-[a-(piperidino)- EXAMPLE 56 3 .6-Bis-l a-( hexamethyleneimino )-butyryl-amino]- acridine A solution of 6.0 gm of 3.6bis-(a-bromobutyryl- EXAMPLEGZ Using a procedure analogous to that described in Example 56. 60% of theory of 3.6-bis-[a-(l'.2.5.6'- tetrahydropyridino)-butyryl-amino]-acridine hemihydrate. an amorphous powder (precipitated from dilute hydrochloric acid with aqueous ammonia). was obtained from 3.6-bis-(a-chlorobutyryl-amino-acridine and l.2.5.o-tetrahydropyridinc EXAMPLE 63 Using a procedure analogous to that described in Exwhich had a melting point of l l6l 18C.

EXAMPLE 57 Using a procedure analogous to that described in Example 56. 78% of theory of 3.6-bis-l(a-pipcridinobutyryl )-amino l-acridine hemihydrate. m.p. l()3l06C (recrystallized from ethanol/water). was obtained from 3 .6-bis-( a-chlorobutyryl-amino acridine and pipcridine.

EXAMPLE 58 Using a procedure analogous to that described in Example 56. 8071 of theory of 3.6-bis-[z-(2-methylpiperidino)-butyryl-aminol-acridine hemihydrate. m.p. l22-l24C (recrystallized from ethanol/water). was obtained from 3 .6-bis-( a-chlorobutyryl-amino acridine and Z-methyI-piperidine.

EXAMPLE 59 Using a procedure analogous to that described in Example 56. 82% of theory of 3.6-bis-[a-(3'-methylpiperidino)-butyryl-aminol-acridine hydrate. m.p. l20l25C (recrystallized from ethanol/water), was

obtained from 3.6-bis-(a-chlorobutyryl-amino)- acridine and 3-methyl-piperidine.

EXAMPLE 60 Using a procedure analogous to that described in Example 56. 58% of theory of 3.6-bis-[a-(4-methyl piperidino)-butyryl-amino]-acridine hemihydrate m.p. l05l08C (recrystallized from ethanol/water), was obtained from 3,6-bis-(a-chlorobutyryl-amino)- acridine and 4-methyl-piperidine.

EXAMPLE 6] Using a procedure analogous to that described in Example 56, 30% of theory of 3,6-bis-[a-(N-methylcyclohexyl-amino)-butyryl-aminoJ-acridine. an amorphous powder (precipitated from dilute hydrochloric acid with aqueous ammonia), was obtained from 3.6- bis-(a-chlorobutyryl-amino)-acridine and N- cyclohexyl-methylamine.

ample 56, 82.292 of theory of 3,6-bis-[(ahexamethyleneimino-butyryl)-amino]-acridine, m.p. ll6l 18C (recrystallized from ethanol/water), was obtained from 3 .6-bis-( a-chlorobutyryl-amino acridinc and hexamethyleneimine.

EXAMPLE 64 3.6-Bis-[(a-l .2,5,6-tetrahydropyridino-isobutyryl)- amino]-acridine 1% H O 9.8 gm of l.2.5,o-tetrahydro-pyridine were added to a solution of 6.0 gm of 3.6-bis-(a-bromoisobutyrylamino)-acridine in 30 ml of dimethylformamide. and the mixture was allowed to stand for 5 hours at C. Thereafter. the reaction solution was allowed to cool and was then stirred into 600 ml of water. The precipitate formed thereby was collected. dissolved in l()() ml of l N hydrochloric acid. and the resulting solution was first diluted with 50 ml of water and then admixed with lOO ml of l N ammonia. The precipitate formed thereby was collected and recrystallized first from 200 ml of ethanol and then from ml of water. yielding 5.0 gm (82% of theory) of the compound of the formula v which had a melting point of l l7l22C.

EXAMPLE 65 Using a procedure analogous to that described in Example 64. 70.9% of theory of 3,6-bis-[(a-piperidinoisobutyryl)-amino]-acridine trihydrate. m.p. l3ll37C (recrystallized from ethanol), was obtained from 3,6-bis-(a-chloroisobutyryl-amino)- acridine and pipcridine.

EXAMPLE 66 Using a procedure analogous to that described in Example 64, 6471 of theory of 3.6-bis-[(ahexamethyleneimino-isobutyryl)-amino]-acridine 2.5 H 0. m.p. 100- 1 02C (recrystallized from ethanol/water). was obtained from 3,6-bis-(a-chloroisobutyrylamino)-acridine and hexamethyleneimine.

obtained EXAMPLE 67 Using a procedure analogous to that described in Example 64. 55.571 of theory of 3.6-bis-[ (oz-2- methylpiperidino-isobutyryl )-amino l-acridine. m.p. l25l28C (recrystallized from ethanol/water). was obtained from acridine and Z-methyl-piperidine.

EXAMPLE 68 Using a procedure analogous to that described in Ex ample 64. 60% of theory of t 3.6-bis-[(oz-3- mcthylpiperidino-isobutyryl)-amino]-acridine. m.p. l()7-l 10C (recrystallized from ethanol/water). was obtained from 3.6-bis-(oz-chloroisobutyryl-amino)- acridine and 3-methyl-piperidine.

EXAMPLE 69 Using a procedure analogous to that described in Example 64. 52% of theory of 3.6-bis-[(a-4 methylpiperidinoisobutyryl)-aminoI-acridine. m.p. l33-l35C (recrystallized from ethanol/water). was

from 3.6-bis-(a-chloroisobutyryl-amino)- acridine and 4-mcthyl-piperidine.

The compounds of the present invention. that is. those embraced by formula I above and their non-toxic. pharmacologically acceptable acid addition salts. have useful pharmacodynamic properties. More particu larly. the compounds of the instant invention induce or stimulate the formation and release of interferon in vitro. as well as in vivo in warm-blooded animals. such as mice.

Particularly effective in this respect are those compounds of the formula I wherein R is hydrogen. R and R are methyl. ethyl. piperidino or cyelohexyl. and A is lower alkylene.

Interferon is a protein formed during the interaction of animal cells with viruses. which is capable of conferring on fresh animal cells of the same species a longlasting resistance to infection with a wide range of viruses. In other words. the activity of an interferon is non-specific with respect to viruses. but specific with respect to the particular animal species.

In the absence of direct prophylactic or therapeutic methods for effectively combatting various virus infections. pharmacologists have long searched for compounds which are capable of significantly stimulating the formation of interferon. Although a number of compounds have been suggested for this purpose. such as living or killed viruses. endotoxin. phytohemagglutinin. trachoma and double-strand complexes of polyinosinic acid and polycytidylic acid. the utility of these substances for the treatment of virus infections is significantly restricted due to serious drawbacks, such as low activity.

The effectiveness of the compounds of the present invention to stimulate the formation of interferon is illustrated by the following tests:

The test compound was administered perorally. with the aid of an esophageal sound. to a group of three to five SPF-strain laboratory mice of about gm body weight. For this purpose the test compound was either dissolved in water or aqueous 20% acetic acid. or. in case of an insoluble compound. suspended in these vehicles after addition of 0.4% of methylcellulose. The dosage levels were 250 and mgm/kg. 24 hours after administration of the test compound. the thorax of the 3.6-bis-(a-chlororisobutyryl-amino)- animals was opened the blood was withdrawn by heart puncture. the blood from all the animals was pooled. and the serum was prepared.

The serum thus obtained was investigated for interferon content in a tissue culture. For this purpose. monolayercultures of tissue cells from mice of the L-929 lineage were incubated for 24 hours with the serum sample under investigation. Each serum was tested in five different stages of dilution. and the test for each stage of dilution was repeated 3 times. Thereafter. the cultures were infested with vesicular stomatitis virus. and the virus propagation was determined 48 hours later by dyeing the cell turf with gentiana violet and counting the plaques which had formed.

The values thus obtained were plotted on a graph of dilution vs. number of plaques. and the degree of dilution which produced a 50% inhibition in the number of plaques formed in comparison to a serum obtained from untreated controls was graphically determined and was considered. by definition. to contain one biological unit. In order to be able to compare different tests with each other. a mouse interfron standard was always tested at the same time. and deviations. if any. from the theoretical value were corrected accordingly. The following table shows the results obtained for a representative group of compounds of the present invention, where 3 .o-bis-l N.N-diethylamino-acetyl )-amino acridine.

Serum of untreated controls: to maximum 6 units/ml. Thus, by virtue of their interferon production inducing activity. the compounds of the present invention are useful and effective for combatting a wide variety of virus infections in warm-blooded animals. In addition to vesicular stomatitis virus. the compounds of the invention will also effectively combat other viruses. such as arbor viruses. picona viruses. herpes virus. pox viruses, myxoviruses and the like.

Since interferon is, to a certain extent. also known to be effective against non-viral pathogens. such as Chlamydia and protozoa (for example, the cause of psittacosis. the TRlC'agent, toxoplasma gondii and plasmodium berghei), the interferon production inducers of the present invention are also believed to be useful for combatting non-viral infections and non-viral benign tumors.

. 23 l For pharmaceutical purposes the compou ndsaeeording to the presentinvention are administere'dtowarm blooded animals perorally or parenterally as active i ngredients in customary dosage unit compositions, that is. compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the activeingredient, such as tablets,

coated pills. capsules, wafers. powders. solutions. suspensions. emulsions,'syrups. suppositories and the like. One effective interferon-producing dosage unit of .the compounds according tothe present invention is from L66 to 16.7 'mgnt/kg body weight. preferably 4.15 to 8.3.mgm/kg body weight.

The following examples illustrate a few'pharmaceutical dosage unit compositions comprising a compound of the present invention as an active ingredient and. represent the best modes contemplated of puttingtheinvention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 70 Coated pills The pill core composition is compounded from the following ingredients:

3 .6-Bisl N .N-diethylamino-aeetyl aminol-acridine trihydroehloride 500.0 parts Lactose 200.0

Corn starch 80.0 Gelatin 12.0 Magnesium stearate 8.0

' Total soon parts Preparation:

with a thin shell consisting essentially of a mixture of sugar. titaniumdidoxide. talcum and gum arabic. and finally polished with beeswax. Each coated pill contains 500 mgm of the acridine compound and is an oral dosage unit composition with effective interferon production inducing action.

EXAMPLE 7] Tablets The tablet composition is compounded from the following ingredients:

3.6-Bis-I 2'-N.N-diethylamino-propionyl amino l-acridine trihydrochloride dihydrate 500.0 parts Lactose 2000 Corn starch l30.0 Soluble starch l2.0 Magnesium stearate 8.0

Total 850.0 parts Preparation:

The acridine compound and the magnesium stearate are intimately admixed with each other. the mixture is granulated with an aqueous solution of the soluble starch. the granulate is dried and thoroughly admixed conventional tablet'making machine Each tablet con i 'w ith 'the. lactoseandthe corn stareh. and the resulting composition is compressed into"850.mgm-tablets it t-a tains 500 mgm of the acridine compound andisan oral dosage unit composition with effective .interferon production inducing action."

Solution I EXA LBI E. 7

v Capsules y The capsule filler composition is compounded from the following ingredients:

' 'The acridinecompoundand the gelatin are admtxe' with each other. the -mixture is granulatedwifthlan;

aqueous solution of gelatin. the granulate'is dried. 502 mgm-portions of'the dry granulate are'filled into? gelatin capsules of suitable size:Each geapsulecojntain 500 mgm of the'aeridine cornpound andis oral dos age unit composition with effectiveinte rferon produ tion inducing action; I EXAMPLE 73 The solution is compounded from the followirig in gredients: Y

3.6-Bis-I N-cyclohexyl-methylamino- Distilled water q.s.ad

Preparation: v I i The sodium hydrogen phosphate. the disodium hydrogen phosphate, the saccharin sodium. the sorbitol and the acridine compound are dissolved in about 300 ,parts by volume of distilled water (solution I).

The two p-hydroxy-benzoates and the flavoring are dissolved in the ethanol (solution ll).

Solution 1 is admixed with solutionll. and the mixed solution'is diluted with distilled water to 500 parts by volume.

Each 5 ml ofthe solution contain 250 mgm of the acridine compound and are an oral dosage unit composition with effective interferon production inducing action.

Analogous results are obtained when any one of the other acridine derivatives embraced by formula I or a non-toxic. pharmacologically acceptable acid addition salt thereof is substituted for the particular acridine compound in Examples through 73. Likewise. the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above. and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to 7 meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof. it will 25 26 be readily apparent to others skilled in the art that the 2. A compound of claim I, wherein invention is not limited to these particular emhodi- R is hydrogen. ments. and that various changes and modifications may R and R are each methyl. ethyl-or c'yclohexyl, and be made without departing from the spirit of the inven- A is lower alkylene or phenyl-lower alkylene. tion or the scope of the appended claims. 5 3. A compound of claim 2, which is 3.6-bis-[(N,N-

diethylamino-acetyl)-amino]-acridine or a non-toxic.

We clzl pbarmacologically acceptable acid addition salt 1. A compound of the formula thereof.

0 o R'\ I \N ll I/R", N-:\-( HN NH-(A\ R wherein 4. A compound otclaim 2. which is 3,6-bis-[ 2'-N N- R is hydrogen or methyl. diethylamino-propionyl)-amino}-acridine or a nontoxic. pharmacologically acceptable acid addition salt thereof.

5. A compound of claim 2. which is 3.6-bis-{(N- cyclohexyl'methylamino-acetyl )-amino ]-acrridine or a A is lower lkylenc phenyl'lower HQ/lent or non'toxic. pharmacologically acceptable acid addition non-toxic. pharmacologically acceptable acid addi- Salt h f tion salt thereof. l

R and R are each hydrogen. lower alkyl. hydroxylower alkyl, lower alkylamino-lmver alkyl, 38 carbon cycloalkyl. bcnzyl. or phenyl, and 

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1, wherein R1 is hydrogen, R2 and R3 are each methyl, ethyl or cyclohexyl, and A is lower alkylene or phenyl-lower alkylene.
 3. A compound of claim 2, which is 3,6-bis-((N,N-diethylamino-acetyl)-amino)-acridine or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 4. A compound of claim 2, which is 3,6-bis-((2''-N,N-diethylamino-propionyl)-amino)-acridine or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 5. A compound of claim 2, which is 3,6-bis-((N-cyclohexyl-methylamino-acetyl)-amino)-acrridine or a non-toxic, pharmacologically acceptable acid addition salt thereof. 